Project Summary: As human life expectancy gradually increases, it has become critical to understand the neural mechanisms by which brain function deteriorates in progressive neurodegenerative disorders. Mouse models of neurodegenerative disorders can be very useful to investigate the mechanisms underlying the sensorimotor and cognitive deficits associated with neurodegenerative disorders. Recent studies indicate that functional alterations in neuronal circuits may occur before neuronal degeneration and may underlie many of the behavioral symptoms associated with neurodegenerative disorders and may be reversible. We have been developing a new electrophysiological approach that allows us to obtain multi-site, long-term simultaneous recordings of the activity of large populations of single neurons in awake behaving mice. We implant arrays of isonel-coated tungsten microwires (35 or 5Q\an, up to 48 per mouse) in multiple brain areas of the same animal. Our preliminary experiments revealed that several well-isolated single units and multi-unit activity can be obtained from a very high number of implanted electrodes. Concomitantly, we have also measured local field potentials (LFP) in the same areas by low-pass filtering the data (0.1 to 400Hz range). Perhaps more importantly, we have demonstrated that these chronic implants are so well tolerated by the animal and its brain that often many single units can be recorded more than 6 months after the initial implantation surgery. To further corroborate this approach, we have already used it to investigate the neural plasticity underlying motor skill learning in WT mice. In the first section of this proposal, we plan to further develop this technique by: a) using high density arrays to increase the number of channels per mouse, b) testing several types of array design to optimize the number and quality of isolation of single neurons per channel and c) testing methodology and software for single unit isolation and visualization (with Pfexon, Inc., Texas). Relevance: Once fully developed, we propose to use this new methodology to test the hypothesis that physiological alterations at the cellular and circuit level (even before severe neurodegeneration) underlie the behavioral deficits in mouse models of neurodegenerative disorders. We believe that this unique approach will allow the integration of molecular, cellular, systems, and behavioral data in the same animal, in order to produce a more complete understanding of the progression of deficits associated with a variety of neurological disorders.